GONADOTROPIN-RELEASING HORMONE ACTION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。自从20世纪70年代初分离出促性腺激素释放激素（GnRH）以来，基础和临床发现已经提出了GnRH类似物的用途。其中包括子宫内膜异位症/纤维瘤、多囊卵巢疾病、围绝经期、卵巢和睾丸的保护（即，化疗期间）、辅助生殖、性早熟、男性和女性节育、前列腺癌、卵巢癌和乳腺癌、隐睾症和其他病症。GnRH作用的研究为神经内分泌肽领域提供了大量有用的基础信息。此外，科学和专利文献中描述了近10，000种具有生物活性的GnRH类似物，为理解结构-活性关系提供了一个精致的数据库;这些类似物包括定义明确的完全激动剂和完全拮抗剂，其中许多是代谢稳定的或具有其他理想的特性。对这种激素的作用机制的更好理解可能会带来改进药物的机会（即，副作用更少、口服活性且更便宜）和更具体的疗法。“非传统”办法也有潜力;本提案介绍了其中一些办法。这项研究的具体目标将促进我们的基本理解，并将确定新的网站和方法可能适合治疗干预。这些措施包括：化学计量学和GnRH受体-受体相互作用的作用; II. GnRH受体与效应子和其他调节蛋白的偶联; III. GnRH刺激的启动子表达的实时动态检查; IV.基于部分激动的治疗方法; V.灵长类动物模型中的生理终点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Since isolation of gonadotropin releasing hormone (GnRH) in the early 1970s, basic and clinical discoveries have presented uses for GnRH analogs. Among these are treatments for endometriosis/fibroids, polycystic ovary disease, perimenopause, protection of the ovary and testes (i.e., during chemotherapy), assisted reproduction, precocious puberty, male and female birth control, prostatic, ovarian and mammary carcinomas, cryptorchidism, and other conditions. Studies of GnRH action have provided a great deal of useful, basic information to the field of neuroendocrine peptides. In addition, nearly 10,000 biologically active GnRH analogs are now described in the scientific and patent literature, providing an exquisite database for understanding structure-activity relations; these analogs include well-defined full agonists and full antagonists, many of which are metabolically stable or have other desirable characteristics. Improved understanding of the mechanism of action of this hormone will likely lead to opportunities for improved drugs (i.e., fewer side effects, orally active and cheaper) and more specific therapies. "Non-traditional" approaches also have potential; approaches involving some of these are described in the present proposal. The specific aims of this study will advance both our basic understanding and will identify new sites and approaches potentially amenable to therapeutic intervention. These include: I. Stoichiometry and role of GnRH receptor-receptor interactions; II. GnRH receptor coupling to effectors and other regulatory proteins; III. Real-time dynamic examination of GnRH-stimulated promoter expression; IV. Therapeutic approaches based on partial agonism; V. Physiological endpoints in a primate model.